Abstract
Background
SLCO-encoded transporters have been associated with progression to castration-resistant prostate cancer (CRPC) after initiation of androgen deprivation therapy (ADT). Although expressed at lower levels than in CRPC tissues, SLCO-encoded transporters may also play a role in response of primary prostate cancer (PCa) to ADT and biochemical recurrence.
Methods
We systematically explored expression of the 11 human SLCO genes in a large sample of untreated and ADT-treated normal prostate (NP) and primary PCa tissues, including tumors treated with neoadjuvant abiraterone.
Results
Transporters with the most recognized role in steroid uptake in PCa, including SLCO2B1 (DHEAS) and 1B3 (testosterone), were consistently detected in primary PCa. SLCO1B3 was nearly 5-fold higher in PCa vs NP with no difference in Gleason 3 vs 4 and no change with ADT. SLCO2B1 was detected at 3-fold lower levels in PCa than NP but was nearly 7-fold higher in Gleason 4 vs Gleason 3 and increased 3-fold following ADT (pā<ā0.05 for all).
Conclusions
We observed clear differences in SLCO expression in PCa vs NP samples, in Gleason 4 vs Gleason 3 tumors, and in ADT-treated vs untreated tissues. These findings are hypothesis generating due to small sample size, but suggest that baseline and ADT-induced changes in PCa OATP expression may influence steroid uptake and response to ADT, as well as uptake and response to drugs such as abiraterone and docetaxel which are also subject to OATP-mediated transport and are now being routinely combined with ADT in the metastatic castration sensitive setting.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 4 print issues and online access
$259.00 per year
only $64.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447ā54.
Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab. 2006;91:3850ā6.
Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67:5033ā41.
Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflug Arch. 2004;447:653ā65.
Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693ā705.
Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol. 2012;165:1260ā87.
Arakawa H, Nakanishi T, Yanagihara C, Nishimoto T, Wakayama T, Mizokami A, et al. Enhanced expression of organic anion transporting polypeptides (OATPs) in androgen receptor-positive prostate cancer cells: possible role of OATP1A2 in adaptive cell growth under androgen-depleted conditions. Biochem Pharmacol. 2012;84:1070ā7.
Hamada A, Sissung T, Price DK, Danesi R, Chau CH, Sharifi N, et al. Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in caucasian patients with androgen-independent prostatic cancer. Clin Cancer Res. 2008;14:3312ā8.
Wang X, Harshman LC, Xie W, Nakabayashi M, Qu F, Pomerantz MM, et al. Association of SLCO2B1 genotypes with time to progression and overall survival in patients receiving androgen-deprivation therapy for prostate cancer. J Clin Oncol. 2016;34:352ā9.
Green SM, Kaipainen A, Bullock K, Zhang A, Lucas JM, Matson C, et al. Role of OATP transporters in steroid uptake by prostate cancer cells in vivo. Prostate Cancer prostatic Dis. 2017;20:20ā7.
Sissung TM, Ley AM, Strope JD, McCrea EM, Beedie S, Peer CJ, et al. Differential expression of OATP1B3 mediates unconjugated testosterone influx. Mol Cancer Res. 2017;15:1096ā105.
Yang M, Xie W, Mostaghel E, Nakabayashi M, Werner L, Sun T, et al. SLCO2B1 and SLCO1B3 may determine time to progression for patients receiving androgen deprivation therapy for prostate cancer. J Clin Oncol. 2011;29:2565ā73.
Cho E, Montgomery RB, Mostaghel EA. Minireview: SLCO and ABC transporters: a role for steroid transport in prostate cancer progression. Endocrinology . 2014;155:4124ā32.
Wright JL, Kwon EM, Ostrander EA, Montgomery B, Line DW, Vessella RL, et al. Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SCLO1B3 and SLCO2B1 on prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev. 2011;20:619ā27.
Pressler H, Sissung TM, Venzon D, Price DK, Figg WD. Expression of OATP family members in hormone-related cancers: potential markers of progression. PLoS One. 2011;6:e20372.
Taplin ME, Montgomery B, Logothetis CJ, Bubley GJ, Richie JP, Dalkin BL, et al. Intense androgen-deprivation therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk prostate cancer: results of a randomized phase II neoadjuvant study. J Clin Oncol. 2014;32:3705ā15.
Mostaghel EA, Nelson PS, Lange P, Lin DW, Taplin ME, Balk S, et al. Targeted androgen pathway suppression in localized prostate cancer: a pilot study. J Clin Oncol. 2014;32:229ā37.
Sowalsky AG, Ye H, Bhasin M, Van Allen EM, Loda M, Lis RT, et al. Neoadjuvant-intensive androgen deprivation therapy selects for prostate tumor foci with diverse subclonal oncogenic alterations. Cancer Res. 2018;78:4716ā30.
Nishiyama T, Ikarashi T, Hashimoto Y, Suzuki K, Takahashi K. Association between the dihydrotestosterone level in the prostate and prostate cancer aggressiveness using the Gleason score. J Urol. 2006;176(4 Pt 1):1387ā91.
Terakawa T, Katsuta E, Yan L, Turaga N, McDonald K-A, Fujisawa M, et al. High expression of SLCO2B1 is associated with prostate cancer recurrence after radical prostatectomy. Oncotarget. 2018;9:14207ā18.
Miyoshi Y, Uemura H, Umemoto S, Sakamaki K, Morita S, Suzuki K, et al. High testosterone levels in prostate tissue obtained by needle biopsy correlate with poor-prognosis factors in prostate cancer patients. BMC Cancer. 2014;14:717.
Grube M, Kock K, Karner S, Reuther S, Ritter CA, Jedlitschky G, et al. Modification of OATP2B1-mediated transport by steroid hormones. Mol Pharmacol. 2006;70:1735ā41.
Konig J. Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms. Handb Exp Pharmacol. 2011;201:1ā28.
Visser WE, Friesema EC, Visser TJ. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol. 2011;25:1ā14.
Hsieh ML, Juang HH. Cell growth effects of triiodothyronine and expression of thyroid hormone receptor in prostate carcinoma cells. J Androl. 2005;26:422ā8.
Roth M, Timmermann BN, Hagenbuch B. Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab Dispos: Biol fate Chem. 2011;39:920ā6.
Liao S, Umekita Y, Guo J, Kokontis JM, Hiipakka RA. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Lett. 1995;96:239ā43.
de Morree E, van Soest R, Aghai A, de Ridder C, de Bruijn P, Ghobadi Moghaddam-Helmantel I, et al. Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation. Prostate. 2016;76:927ā36.
Iusuf D, Hendrikx JJ, van Esch A, van de Steeg E, Wagenaar E, Rosing H, et al. Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int J Cancer. 2015;136:225ā33.
Rodrigues AC. Efflux and uptake transporters as determinants of statin response. Expert Opin Drug Metab Toxicol. 2010;6:621ā32.
Alfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nat Rev Urol. 2017;14:107ā19.
Juang HH, Lin YF, Chang PL, Tsui KH. Cardiac glycosides decrease prostate specific antigen expression by down-regulation of prostate derived Ets factor. J Urol. 2010;184:2158ā64.
He XX, Tu SM, Lee MH, Yeung SC. Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol. 2011;22:2640ā5.
Hoption Cann SA, Qiu Z, van Netten C. A prospective study of iodine status, thyroid function, and prostate cancer risk: follow-up of the First National Health and Nutrition Examination Survey. Nutr Cancer. 2007;58:28ā34.
Mondul AM, Weinstein SJ, Bosworth T, Remaley AT, Virtamo J, Albanes D. Circulating thyroxine, thyroid-stimulating hormone, and hypothyroid status and the risk of prostate cancer. PLoS One. 2012;7:e47730.
Chan YX, Knuiman MW, Divitini ML, Brown SJ, Walsh J, Yeap BB. Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer. Eur J Endocrinol. 2017;177:297ā308.
Zhang S, Hsieh ML, Zhu W, Klee GG, Tindall DJ, Young CY. Interactive effects of triiodothyronine and androgens on prostate cell growth and gene expression. Endocrinology . 1999;140:1665ā71.
Tsui KH, Hsieh WC, Lin MH, Chang PL, Juang HH. Triiodothyronine modulates cell proliferation of human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2. Prostate. 2008;68:610ā9.
van der Deure WM, Hansen PS, Peeters RP, Kyvik KO, Friesema EC, Hegedus L, et al. Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation. Endocrinology . 2008;149:5307ā14.
Lee HH, Leake BF, Teft W, Tirona RG, Kim RB, Ho RH. Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance. Mol Cancer Ther. 2015;14:994ā1003.
de MorrƩe ES, Bƶttcher R, van Soest RJ, Aghai A, de Ridder CM, Gibson AA, et al. Loss of SLCO1B3 drives taxane resistance in prostate cancer. Br J Cancer. 2016;115:674.
Nishiyama T, Ikarashi T, Hashimoto Y, Wako K, Takahashi K. The change in the dihydrotestosterone level in the prostate before and after androgen deprivation therapy in connection with prostate cancer aggressiveness using the Gleason score. J Urol. 2007;178(4 Pt 1):1282ā8. discussion 8-9
Mostaghel EA, Cho E, Zhang A, Alyamani M, Kaipainen A, Green S, et al. Association of tissue abiraterone levels and SLCO genotype with intraprostatic steroids and pathologic response in men with high-risk localized prostate cancer. Clin Cancer Res. 2017;23:4592ā601.
Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A. Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol. 2010;28:4562ā7.
Mout L, de Wit R, Stuurman D, Verhoef E, Mathijssen R, de Ridder C, et al. Testosterone diminishes cabazitaxel efficacy and intratumoral accumulation in a prostate cancer xenograft model. EBioMedicine . 2018;27:182ā6.
Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev. 2010;62:1ā96.
Murray M, Zhou F. Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease. Br J Pharmacol. 2017;174:1908ā24.
Lu R, Kanai N, Bao Y, Wolkoff AW, Schuster VL. Regulation of renal oatp mRNA expression by testosterone. Am J Physiol. 1996;270(2 Pt 2):F332ā7.
Aleksunes LM, Klaassen CD. Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARalpha-, and Nrf2-null mice. Drug Metab Dispos: Biol fate Chem. 2012;40:1366ā79.
Thakkar N, Lockhart AC, Lee W. Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy. AAPS J. 2015;17:535ā45.
Nyquist MD, Prasad B, Mostaghel EA. Harnessing solute carrier transporters for precision oncology. Molecules. 2017;22. pii: E539.
Acknowledgements
The authors wish to acknowledge technical assistance from Jennifer Noteboom and Lori Kollath who assisted with provision of clinical outcome data, as well as Drs. Daniel Lin, William Ellis, and Jonathan Wright for supporting collection of excess frozen prostate tissue at time of radical prostatectomy.
Funding
This work was supported by NIH grants (Pacific Northwest Prostate Cancer SPORE P50 CA097186 to LT, PSN, RBM, EAM; FHCRC Cancer Center Support Grant 5P30 CA015704-40 (PSN, EAM); DF/HCC SPORE P50 CA090381 to AGS, HY, MET, and SPB; P01 CA163227 to EAM, PSN, SPB); Prostate Cancer Foundation (Challenge Awards to EAM, PSN, MET, SPB; Young Investigator Awards to AGS, HE, EAM); Department of Defense Prostate Cancer Research Program (W81XWH-11-2-0154 to EAM; W81XWH-13-1-0267 and W81XWH-16-1-0433 to AGS; W81XWH-16-1-0431 to SPB and W81XWH-16-1-0432 to MET), the Intramural Research Program of the NIH, National Cancer Institute (AGS), and the Department of Veterans Affairs Puget Sound Health Care System (EAM).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisherās note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Alsinnawi, M., Zhang, A., Bianchi-Frias, D. et al. Association of prostate cancer SLCO gene expression with Gleason grade and alterations following androgen deprivation therapy. Prostate Cancer Prostatic Dis 22, 560ā568 (2019). https://doi.org/10.1038/s41391-019-0141-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41391-019-0141-6
This article is cited by
-
Early upregulation of AR and steroidogenesis enzyme expression after 3 months of androgen-deprivation therapy
BMC Urology (2020)
-
Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer
British Journal of Cancer (2020)